Crystal modifications of elobixibat

ABSTRACT

The present invention relates to crystal modifications of N-{(2R)-2-[({[3,3-dibutyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl]oxy}acetyl)amino]-2-phenylethanolyl}glycine (elobixibat).

CROSS REFERENCE TO RELATED APPLICATION

This application is a continuation of U.S. patent application Ser. No.15/519,808, filed Apr. 17, 2017 which is a National Stage Applicationunder 35 U.S.C. § 371 and claims the benefit of InternationalApplication No. PCT/EP2015/074573, filed Oct. 23, 2015, which claimspriority to European Application No. 14190290.8, filed Oct. 24, 2014,the disclosures of which are incorporated herein by reference in theirentireties.

The present invention relates to crystal modifications ofN-{(2R)-2-[({[3,3-dibutyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl]oxy}acetyl)amino]-2-phenylethanolyl}-glycine(elobixibat).

BACKGROUND

WO 02/50051 discloses the compound1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-1′-phenyl-1′-[N′-(carboxymethyl)carbamoyl]methyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine(elobixibat; IUPAC name:N-{(2R)-2-[({[3,3-dibutyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl]oxy}acetyl)amino]-2-phenylethanolyl}glycine).This compound is an ileal bile acid transporter (IBAT) inhibitor, whichcan be used in the treatment or prevention of diseases such asdyslipidemia, constipation, diabetes and liver diseases. According tothe experimental section of WO 02/50051, the last synthetic step in thepreparation of elobixibat consists of the hydrolysis of a tert-butoxylester under acidic conditions. The crude compound was obtained byevaporation of the reaction mixture under reduced pressure andpurification of the residue by preparative HPLC usingacetonitrile/ammonium acetate buffer (50:50) as eluent (Example 43).After freeze drying the product, no crystalline material was identified.

It would be desirable to discover forms of elobixibat that aresufficiently robust to be suitable for formulation as a pharmaceutical.

Various crystal modifications may have disadvantages including residualsolvents, a variable degree of crystallinity and difficulties inhandling and formulating. Thus, there is a need for crystalmodifications of elobixibat having improved properties with respect tostability, bulk handling and solubility. It is therefore an object ofthe present invention to provide a stable crystal modification ofelobixibat with good crystallinity and other formulation properties.

SUMMARY OF THE INVENTION

The invention provides various crystal modifications of elobixibat. Thisinvention is based in part on the discovery that elobixibat tends toform highly crystalline solvated structures with many solvents. As seenin the examples below, a number of the crystal modifications formcrystalline ansolvates when the solvent is removed from the crystal.Several of these crystals can then form hydrates, following exposure toa sufficiently humid environment. It is surprising that these crystalmodifications contain a substantially stoichiometric amount of solvatein view of their ability to lose and regain solvate molecules withoutdissolution and recrystallization.

In one aspect, the crystal modification is a crystalline form ofelobixibat that is capable of containing or actually contains asubstantially stoichiometric amount of water. Preferably, thesubstantially stoichiometric amount of water is not one mole per mole ofelobixibat. A substantially stoichiometric amount of water is an amountthat is within 15 mol % of a whole number value. Thus, for example, adihydrate includes 1.7-2.3 moles of water associated with each mole ofelobixibat in a crystal. The amount of water calculated herein excludeswater adsorbed to the surface of the crystal. The invention alsoincludes anhydrates of elobixibat.

The invention further provides methods of treating a condition describedherein and use of the crystal modifications described herein in treatinga condition described herein and in the manufacture of a medicament forthe treatment of a condition described herein.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the X-ray powder diffractogram of crystal modification Fproduced from methyl isobutyl ketone.

FIG. 2 shows the X-ray powder diffractogram of crystal modification Fproduced from ethyl acetate.

FIG. 3 shows the X-ray powder diffractogram of crystal modification Cproduced from acetone:water 1:1 v/v.

FIG. 4 shows the X-ray powder diffractogram of crystal modification Cproduced from ethyl acetate.

FIG. 5 shows the X-ray powder diffractogram of crystal modification L.

FIG. 6 shows the X-ray powder diffractogram of crystal modification N.

FIG. 7 shows the X-ray powder diffractogram of crystal modification E.

FIG. 8 shows the X-ray powder diffractogram of crystal modification G.

FIG. 9 shows the X-ray powder diffractogram of crystal modification H.

FIG. 10 shows the DVS isotherm plot of crystal modification F. The fourcurves show sorption and desorption for two consecutive DVS-cycles. Thex-axis shows the % RH change and the y-axis shows the sample respond inweight % water.

FIG. 11 shows the DVS isotherm plot of crystal modifications C and E.The four curves show sorption and desorption for two consecutiveDVS-cycles. The x-axis shows the % RH change and the y-axis shows thesample respond in weight % water.

FIG. 12 shows the X-ray powder diffractogram of crystal modification D.

FIG. 13 shows the X-ray powder diffractogram of crystal modification M.

FIG. 14 shows the DVS isotherm plot of crystal modification L and N. Thefour curves show sorption and desorption for two consecutive DVS-cycles.The x-axis shows the % RH change and the y-axis shows the sample respondin weight % water.

FIG. 15 shows a conversion diagram for a number of the crystalmodifications described herein.

DETAILED DESCRIPTION OF THE INVENTION

The invention described herein relates to crystal modifications thatwere discovered in extensive studies on elobixibat. While not wishing tobe bound by theory, it is believed that crystalline forms of elobixibatcan be formed from a variety of solvents possessing at least some polarcharacter. Again not wishing to be bound by theory, it is believed thatelobixibat forms crystal structures containing occupied or partiallyoccupied void volumes, where the solvent molecules reside. The voids arein many of these crystals unusual in that they hold substantiallystoichiometric amount of solvate (e.g., hydrate) molecules, yet thesolvate molecules can be removed and replaced without dissolution andrecrystallization of the crystals. It is advantageous to containsubstantially stoichiometric amounts of water, as the water content ofcrystals remains substantially constant even with changes in relativehumidity. In certain embodiments, the water content remainssubstantially constant at RH greater than 20%, 30%, 40% or more. Inother embodiments, the water content remains substantially constant atRH less than 20% or 10%.

In one aspect, the invention relates to a crystalline form ofelobixibat, where the form includes void volumes that are capable ofcontaining a substantially stoichiometric amount of water, such as underconditions of 10% RH and 20° C., 40% RH and 20° C., 58% RH and 20° C.,80% RH and 20° C., or 75% RH and 40° C. The invention includes both thehydrate and anhydrate forms of the relevant crystals. Preferably, thesubstantially stoichiometric amount of water is not one mole per mole ofelobixibat (e.g., 0.7-1.3 mol, 0.8-1.2 mol or 0.9-1.1 moles of water permole of elobixibat). A substantially stoichiometric amount of water isan amount that is within 15 mol % (e.g., 10 mol %, 5 mol %, 2.5 mol %)of a whole number value. Thus, for example, a dihydrate includes1.7-2.3, 1.8-2.2, 1.9-2.1 or 1.95-2.05 moles of water associated witheach mole of elobixibat in a crystal. For an anhydrate, there is lessthan 0.15 moles, less than 0.10 moles or even less than 0.05 or 0.025moles associated with each mole of elobixibat. The amount of watercalculated herein excludes water adsorbed to the surface of the crystal.Void volumes as used herein, refer to channels, layers or more or lessisolated voids in the crystal structure.

In certain embodiments, the invention includes a crystalline anhydrateof elobixibat, where the anhydrate is stable at a relative humidity (RH)of 10% or less or 20% or less at a temperature of 20° C. Such anhydratescan be stable under these conditions for at least 1 hour, 1 day, 1month, 3 months, 6 months, 1 year, 2 years, 3 years or longer. It isadvantageous for certain anhydrates to be stable for these periods underdifferent storage conditions, such as 40% RH and 20° C., 58% RH and 20°C., 80% RH and 20° C., or 75% RH and 40° C. Anhydrates stable at 10% RH(e.g., at 20° C. or 40° C.) are particularly suitable for Zone IIIconditions (hot/dry) or in formulations containing drying agents (e.g.,silica gel, calcium sulfate, calcium chloride, calcium phosphate, sodiumchloride, sodium bicarbonate, sodium sulfate, sodium phosphate,montmorillonite, molecular sieves (beads or powdered), alumina, titania,zirconia, and sodium pyrophosphate), whereas anhydrates stable at 40% RHand above are suitable for Zone I (temperate), II (subtropical) and IV(hot/humid) conditions.

Stability can be assessed as physical stability, chemical stability orboth. Chemical stability refers to the molecule (i.e., elobixibat) notundergoing reaction to a new molecule. Physical stability refers to thecrystal structure not changing over time, which can be measured by oneor more of the techniques discussed herein such as XPRD, and optionallycomplemented by DVS, TGA and DSC.

In one embodiment, the crystalline anhydrate is crystal modification Fhaving an X-ray powder diffraction (XRPD) pattern, obtained withCuKα1-radiation, with at least specific peaks at °2θ positions 6.1±0.2and/or 5.9±0.2. In certain embodiments, the invention relates to crystalmodification F having an XRPD pattern, obtained with CuKα1-radiation,with specific peaks at °2θ positions 6.1±0.2 and 5.9±0.2 and one or moreof the characteristic peaks: 6.6±0.2, 8.3±0.2, and 11.9±0.2. In a moreparticular embodiment, the invention relates to crystal modification Fhaving an XRPD pattern, obtained with CuKα1-radiation, with specificpeaks at °2θ positions 6.1±0.2, 5.9±0.2, 6.6±0.2, 8.3±0.2, and 11.9±0.2.In a further embodiment, the invention relates to crystal modification Fhaving an XRPD pattern, obtained with CuKα1-radiation, withcharacteristic peaks at °2θ positions 6.1±0.2, 5.9±0.2, 6.6±0.2,8.3±0.2, and 11.9±0.2, and one or more of 7.4±0.2, 10.6±0.2, 11.7±0.2,19.2±0.2, and 19.8±0.2. In a yet more particular embodiment, theinvention relates to crystal modification F having an XRPD pattern,obtained with CuKα1-radiation, substantially as shown in FIG. 1 or FIG.2.

In one embodiment, the crystalline anhydrate is crystal modification Chaving an X-ray powder diffraction (XRPD) pattern, obtained withCuKα1-radiation, with at least specific peaks at °2θ positions 12.4±0.2and/or 5.8±0.2. In certain embodiments, the invention relates to crystalmodification C having an XRPD pattern, obtained with CuKα1-radiation,with specific peaks at °2θ positions 12.4±0.2 and 5.8±0.2 and one ormore of the characteristic peaks: 4.8±0.2, 8.2±0.2, 9.9±0.2, 10.9±0.2,16.6±0.2, 19.8±0.2 and 20.6±0.2. In a more particular embodiment, theinvention relates to crystal modification C having an XRPD pattern,obtained with CuKα1-radiation, with specific peaks at °2θ positions12.4±0.2, 5.8±0.2, 4.8±0.2, 8.2±0.2, 9.9±0.2, 10.9±0.2, 16.6±0.2,19.8±0.2 and 20.6±0.2. In a further embodiment, the invention relates tocrystal modification C having an XRPD pattern, obtained withCuKα1-radiation, with characteristic peaks at °2θ positions 12.4±0.2,5.8±0.2, 4.8±0.2, 8.2±0.2, 9.9±0.2, 10.9±0.2, 16.6±0.2, 19.8±0.2 and20.6±0.2, and one or more of 4.1±0.2, 6.7±0.2, 9.5±0.2, 12.6±0.2, and20.7±0.2. In a yet more particular embodiment, the invention relates tocrystal modification C having an XRPD pattern, obtained withCuKα1-radiation, substantially as shown in FIG. 3 or FIG. 4.

In one embodiment, the crystalline anhydrate is crystal modification Lhaving an X-ray powder diffraction (XRPD) pattern, obtained withCuKα1-radiation, with at least specific peaks at °2θ positions 6.4±0.2and/or 12.7±0.2. In certain embodiments, the invention relates tocrystal modification L having an XRPD pattern, obtained withCuKα1-radiation, with specific peaks at °2θ positions 6.4±0.2 and12.7±0.2 and one or more of the characteristic peaks: 4.2±0.2, 8.5±0.2,10.5±0.2, 19.3±0.2 and 19.5±0.2. In a more particular embodiment, theinvention relates to crystal modification L having an XRPD pattern,obtained with CuKα1-radiation, with specific peaks at °2θ positions6.4±0.2, 12.7±0.2, 4.2±0.2, 8.5±0.2, 10.5±0.2, 19.3±0.2 and 19.5±0.2. Ina further embodiment, the invention relates to crystal modification Lhaving an XRPD pattern, obtained with CuKα1-radiation, withcharacteristic peaks at °2θ positions 6.4±0.2, 12.7±0.2, 4.2±0.2,8.5±0.2, 10.5±0.2, 19.3±0.2 and 19.5±0.2, and one or more of 4.8±0.2,5.9±0.2, 12.1±0.2, 12.4±0.2, 13.3±0.2, 13.6±0.2, 17.7±0.2, 19.9±0.2 and21.4±0.2. In a yet more particular embodiment, the invention relates tocrystal modification L having an XRPD pattern, obtained withCuKα1-radiation, substantially as shown in FIG. 5.

In a second aspect, the invention includes a crystalline dihydrate ofelobixibat. Preferably, the dihydrate includes 1.7-2.3, 1.8-2.2, 1.9-2.1or 1.95-2.05 moles of water associated with a crystal per mole ofelobixibat. The amount of water calculated herein excludes wateradsorbed to the surface of the crystal.

In one embodiment, the dihydrate is stable when in contact with water(e.g., a solution where water is the solvent). Such dihydrates may alsoor alternatively be stable in a saturated or nearly saturated atmosphere(i.e., 90%, 95%, 100% RH). Such dihydrates may be stable at temperaturesof 20° C., 40° C., 60° C. or even 75° C. Stability can exist for aperiod of 1 day, 1 week, 1 month, 3 months, 6 months, 1 year, 2 years, 3years or longer. In certain embodiments, the dihydrate is also stable atRH as low as 60%, 40% or even 20% for periods of 1 day, 1 week, 1 month,3 months, 6 months, 1 year, 2 years, 3 years or longer, at temperaturesof 20° C., 40° C., 60° C. or even 75° C.

In another embodiment, which may have a stability as indicated above, adihydrate can be crystallized directly from slurry. In certainembodiments, crystallization can occur following synthesis of elobixibatwithout purification. Exemplary conditions include crystallization with1:1 volume mixtures of methanol or 2-propanol and water at 5° C.Advantages of such direct crystallization include easier purificationand less difficult separation, with an associated lower risk of residualsolvents.

In one embodiment, the crystalline dihydrate is crystal modification Nor E having an X-ray powder diffraction (XRPD) pattern, obtained withCuKα1-radiation, with at least specific peaks at °2θ positions 6.1±0.2and/or 12.0±0.4.

In embodiments where the dihydrate is crystal modification N, the XRPDpattern, obtained with CuKα1-radiation, has specific peaks at °2θpositions 6.1±0.2, 8.0±0.2 and 12.0±0.2; in certain embodiments, theseare the most significant three peaks. In a particular embodiment, theinvention relates to crystal modification N having an XRPD pattern,obtained with CuKα1-radiation, with specific peaks at °2θ positions6.1±0.2, 8.0±0.2 and 12.0±0.2 and one or more of the characteristicpeaks: 4.0±0.2, 10.1±0.2, 20.1±0.2 and 21.0±0.2. In a more particularembodiment, the invention relates to crystal modification N having anXRPD pattern, obtained with CuKα1-radiation, with specific peaks at °2θpositions 6.1±0.2, 8.0±0.2, 12.0±0.2, 4.0±0.2, 10.1±0.2, 20.1±0.2 and21.0±0.2. In a further embodiment, the invention relates to crystalmodification N having an XRPD pattern, obtained with CuKα1-radiation,with characteristic peaks at °2θ positions 6.1±0.2, 8.0±0.2, 12.0±0.2,4.0±0.2, 10.1±0.2, 20.1±0.2 and 21.0±0.2, and one or more of 10.8±0.2,11.4±0.2, 13.3±0.2, 18.0±0.2, 18.5±0.2 and 19.7±0.2. In a yet moreparticular embodiment, the invention relates to crystal modification Nhaving an XRPD pattern, obtained with CuKα1-radiation, substantially asshown in FIG. 6.

In embodiments where the dihydrate is crystal modification E, the XRPDpattern, obtained with CuKα1-radiation, has specific peaks at °2θpositions 6.1±0.2, 12.1±0.2 and 20.9±0.2; in certain embodiments, theseare the most significant three peaks. In a particular embodiment, theinvention relates to crystal modification E having an XRPD pattern,obtained with CuKα1-radiation, with specific peaks at °2θ positions6.1±0.2, 12.1±0.2 and 20.9±0.2 and one or more of the characteristicpeaks: 8.1±0.2, 10.1±0.2, 11.4±0.2, 22.3±0.2 and 22.5±0.2. In a moreparticular embodiment, the invention relates to crystal modification Ehaving an XRPD pattern, obtained with CuKα1-radiation, with specificpeaks at °2θ positions 6.1±0.2, 12.1±0.2, 20.9±0.2, 8.1±0.2, 10.1±0.2,11.4±0.2, 22.3±0.2 and 22.5±0.2. In a further embodiment, the inventionrelates to crystal modification E having an XRPD pattern, obtained withCuKα1-radiation, with characteristic peaks at °2θ positions 6.1±0.2,12.1±0.2, 20.9±0.2, 8.1±0.2, 10.1±0.2, 11.4±0.2, 22.3±0.2 and 22.5±0.2,and one or more of 4.0±0.2, 18.6±0.2, 19.4±0.2, 21.1±0.2. In a yet moreparticular embodiment, the invention relates to crystal modification Ehaving an XRPD pattern, obtained with CuKα1-radiation, substantially asshown in FIG. 7.

The crystal modifications described above may advantageously include oneor more of the following features, such as with respect to amorphousmaterial: lower hygroscopicity, higher chemical stability, higherphysical stability, improved ability to process into a formulation,reduced risk of residual solvent, improved ability to manufacture fromcrude synthesized elobixibat, and reproducible solubility. Many of theseproperties are highly relevant to compounds that are to be used inpharmaceutical preparations, where each formulation containing theactive pharmaceutical ingredient should have the same pharmacologicalproperties.

Elobixibat is an ileal bile acid transporter (IBAT) inhibitor. The ilealbile acid transporter (IBAT) is the main mechanism for re-absorption ofbile acids from the GI tract. Partial or full blockade of that IBATmechanism will result in lower concentration of bile acids in the smallbowel wall, portal vein, liver parenchyma, intrahepatic biliary tree,and extrahepatic biliary tree, including the gall bladder. Diseaseswhich may benefit from partial or full blockade of the IBAT mechanismmay be those having, as a primary pathophysiological defect, symptoms ofexcessive concentration of bile acids in serum and in the above organs.

Thus, in another aspect, the invention also relates to crystalmodifications of elobixibat described herein for use in therapy.

Crystal modifications of elobixibat described herein are useful in theprophylaxis or treatment of hypercholesterolemia, dyslipidemia,metabolic syndrome, obesity, disorders of fatty acid metabolism, glucoseutilization disorders, disorders in which insulin resistance isinvolved, type 1 and type 2 diabetes mellitus, liver diseases, diarrhoeaduring therapy comprising an IBAT inhibitor compound, constipationincluding chronic constipation, e.g. functional constipation, includingchronic idiopathic constipation (CIC) and constipation predominantirritable bowel syndrome (IBS-C). Treatment and prophylaxis ofconstipation is described in WO 2004/089350.

Further potential diseases to be treated with the crystal modificationsof elobixibat described herein are selected from the group consisting ofliver parenchyma, inherited metabolic disorders of the liver, Bylersyndrome, primary defects of bile acid (BA) synthesis such ascerebrotendinous xanthomatosis, secondary defects such as Zellweger'ssyndrome, neonatal hepatitis, cystic fibrosis (manifestations in theliver), ALGS (Alagilles syndrome), progressive familial intrahepaticcholestasis (PFIC), autoimmune hepatitis, primary biliary cirrhosis(PBC), liver fibrosis, non-alcoholic fatty liver disease, NAFLD/NASH,portal hypertension, general cholestasis such as in jaundice due todrugs or during pregnancy, intra- and extrahepatic cholestasis such ashereditary forms of cholestasis such as PFIC1, primary sclerosingcholangitis (PSC), gall stones and choledocholithiasis, malignancycausing obstruction of the biliary tree, symptoms (scratching, pruritus)due to cholestasis/jaundice, pancreatitis, chronic autoimmune liverdisease leading to progressive cholestasis, pruritus of cholestaticliver disease and disease states associated with hyperlipidaemicconditions.

Other diseases to be treated with the crystal modifications ofelobixibat described herein are selected from the group consisting ofhepatic disorders and conditions related thereto, fatty liver, hepaticsteatosis, non-alcoholic steatohepatitis (NASH), alcoholic hepatitis,acute fatty liver, fatty liver of pregnancy, drug-induced hepatitis,iron overload disorders, hepatic fibrosis, hepatic cirrhosis, hepatoma,viral hepatitis and problems in relation to tumours and neoplasmas ofthe liver, of the biliary tract and of the pancreas.

Thus, in one embodiment, the invention relates to crystal modificationsof elobixibat described herein for use in the treatment and/orprophylaxis of a disease or disorder as listed above.

In another embodiment, the invention relates to the use of crystalmodifications of elobixibat described herein in the manufacture of amedicament for the treatment and/or prophylaxis of a disease or disorderas listed above.

In yet another embodiment, the invention relates to a method oftreatment and/or prophylaxis of a disease or disorder as listed above ina warm-blooded animal, comprising administering an affective amount ofcrystal modifications of elobixibat described herein to a warm-bloodedanimal in need of such treatment and/or prophylaxis.

Another aspect of the invention relates to a pharmaceutical compositioncomprising an effective amount of crystal modifications of elobixibatdescribed herein, in association with a pharmaceutically acceptablediluent or carrier.

Yet another aspect of the invention relates to the use of crystalmodifications of elobixibat described herein in the preparation of apharmaceutical composition, comprising admixing the crystal modificationwith a pharmaceutically acceptable diluent or carrier.

The pharmaceutical composition may further comprise at least one otheractive substance, such as an active substance selected from an IBATinhibitor; an enteroendocrine peptide or enhancer thereof; a dipeptidylpeptidase-IV inhibitor; a biguanidine; an incretin mimetic; athiazolidinone; a PPAR agonist; a HMG Co-A reductase inhibitor; a bileacid binder; a TGR5 receptor modulator; a member of the prostone classof compounds; a guanylate cyclase C agonist; a 5-HT4 serotonin agonist;or a pharmaceutically acceptable salt of any one these activesubstances. Examples of such combinations are also described inWO2012/064268.

Crystal modifications of elobixibat will normally be administered to awarm-blooded animal at a unit dose within the range of 5 to 5000 mg persquare meter body area, i.e. approximately 0.1 to 100 mg/kg or 0.01 to50 mg/kg, and this normally provides a therapeutically-effective dose. Aunit dose form, such as a tablet or capsule, will usually contain about1 to 250 mg of active ingredient, such as about 1 to 100 mg, or about 5to 50 mg, e.g. about 1 to 20 mg. The daily dose can be administered as asingle dose or divided into one, two, three or more unit doses. Anorally administered daily dose of an IBAT inhibitor is preferably within0.1 to 1000 mg, more preferably 1 to 100 mg, such as 5 to 15 mg.

The dosage required for the therapeutic or prophylactic treatment willdepend on the route of administration, the severity of the disease, theage and weight of the patient and other factors normally considered bythe attending physician when determining the individual regimen anddosage levels appropriate for a particular patient.

Definitions

The term “crystal modification” refers to a crystalline solid phase ofan organic compound. A crystal modification can be either a solvate oran ansolvate.

The term “solvate” refers to a crystalline solid phase of an organiccompound, which has solvent molecules incorporated into its crystalstructure. A “hydrate” is a solvate wherein the solvent is water.

The term “slurry” refers to a saturated solution to which an overshootof solid is added, thereby forming a mixture of solid and saturatedsolution, a “slurry”.

As used herein, the terms “treatment,” “treat,” and “treating” refer toreversing, alleviating, delaying the onset of, or inhibiting theprogress of a disease or disorder, or one or more symptoms thereof, asdescribed herein. In some embodiments, treatment may be administeredafter one or more symptoms have developed. In other embodiments,treatment may be administered in the absence of symptoms. For example,treatment may be administered to a susceptible individual prior to theonset of symptoms (e.g., in light of a history of symptoms and/or inlight of genetic or other susceptibility factors). Treatment may also becontinued after symptoms have resolved, for example to prevent or delaytheir recurrence.

When reference is made herein to a crystalline compound, preferably thecrystallinity as estimated from X-ray powder diffraction data is greaterthan about 70%, such as greater than about 80%, particularly greaterthan about 90%, more particularly greater than about 95%. In embodimentsof the invention, the degree of crystallinity as estimated by X-raypowder diffraction data is greater than about 98%, preferably greaterthan about 99%, wherein the % crystallinity refers to the percentage byweight of the total sample mass which is crystalline.

Preferably a crystal modification according to the invention issubstantially free from other crystal modifications of the compound.Preferably, the described crystal modifications of elobixibat includesless than, for example, 20%, 15%, 10%, 5%, 3%, or particularly, lessthan 1% by weight of other crystal modifications of elobixibat. Thus,preferably, the solid phase purity of the described crystalmodifications of elobixibat is >80%, >85%, >90%, >95%, >97%, orparticularly >99%.

The invention will now be described by the following examples which donot limit the invention in any respect. All cited documents andreferences are incorporated by reference.

Experimental Methods

X-Ray Powder Diffraction (XRPD) Analysis

Dry samples were lightly ground in an agate mortar, if needed, and werethen smeared out on a sample holder. Slurry samples were added to thesample holder as wet and were analyzed both wet and dry. XRPD data werecollected on a cut Silicon Zero Background Holder (ZBH) or on a PorousAlumina Filter Sample Holder, using a PANalytical X'Pert Prodiffractometer, equipped with an X'celerator or a PIXcel detector. Thesample was spun during analysis and Cu-radiation was used. The followingexperimental settings were used:

Tube tension and current: 40 kV, 50 mA

Wavelength alpha1 (CuKα1): 1.5406 Å

Wavelength alpha2 (CuKα2): 1.5444 Å

Wavelength alpha1 and alpha2 mean (CuKα): 1.5418 Å

Start angle [2 theta]: 1-4°

End angle [2 theta]: 30-40°

Analysis time: 50 s (“1 min scan”), 125 s (“2 min scan”), 192 s (“3 minscan”), 397 s (“6 min scan”), 780 s (“13 min scan”), 1020 s (“17 minscan”), 4560 s (“1 h scan”)

Unless indicated otherwise, when calculating the peak positions from theXRPD-data, the data was first stripped from the contribution from CuKα2and was then corrected against an internal standard (Al₂O₃).

It is known in the art that an X-ray powder diffraction pattern may beobtained having one or more measurement errors depending on measurementconditions (such as equipment, sample preparation or machine used). Inparticular, it is generally known that intensities in an XRPD patternmay fluctuate depending on measurement conditions and samplepreparation. For example, persons skilled in the art of XRPD willrealise that the relative intensities of peaks may vary according to theorientation of the sample under the test and on the type and setting ofthe instrument used. The skilled person will also realise that theposition of reflections can be affected by the precise height at whichthe sample sits in the diffractometer and the zero calibration of thediffractometer. The surface planarity of the sample may also have asmall effect. Hence a person skilled in the art will appreciate that thediffraction pattern presented herein is not to be construed as absoluteand any crystalline form that provides a powder diffraction patternsubstantially identical to those disclosed herein fall within the scopeof the present disclosure (for further information, see R. Jenkins andR. L. Snyder, “introduction to X-ray powder diffractometry”, John Wiley& Sons, 1996).

Dynamic Vapor Sorption (DVS)

Approximately 2-16 mg of the sample was weighed into a metal receptacle,which was then released of static electricity. The metal receptacle waspositioned in a Surface Measurements System Ltd DVS Advantageinstrument. The sample was subjected to two consecutivesorption-desorption cycles, each running from 0-95-0% relative humidity(% RH). One cycle consisted of 21 steps, those between 0-90% RH weretaken in 10% RH each. At each stage the following equilibrium criteriawas used: dm/dt over 5 minutes <0.002% and the minimum and maximum timeat each stage were 10 and 360 min respectively.

The starting material1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-1′-phenyl-1′-[N′-(t-butoxycarbonylmethyl)carbamoyl]methyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepinecan be prepared as described in WO02/50051.

EXAMPLES

Preparation of Form A monohydrate

Form A monohydrate can be prepared according to the methods described inPCT application number PCT/EP2014/058432, filed Apr. 25, 2014, which isreferred to therein as crystal modification IV. Briefly, form A can beprepared by mixing 100 mg of any dry solid material of Elobixibat with 2mL ethanol, in a closed vessel for a week. The solid is then isolatedand dried in vacuum at elevated temperature until the ethanol has beendried off. Finally, the solid is exposed to humid air at ambienttemperature until highly crystalline form A monohydrate has been formed.

Preparation of Form G MIBK Solvate and Form F Anhydrate

102 mg of Elobixibat form A monohydrate was dissolved in 0.5 mL methylisobutyl ketone (MIBK) in a 10 mL test tube at 60° C. N-heptane was thenadded in portions of 0.1 mL over a period of 2 hours. When 0.6 mLn-heptane had been added precipitation occurred. The vessel was thenleft stirred for 4 days until a thick white slurry had formed. Thevessel was cooled to 21-22° C. and then a sample of the slurry waswithdrawn with a Pasteur pipette and put on a cut Silicon zerobackground holder (ZBH). The wet sample was analyzed with XRPD, whichshowed that it consisted of form G MIBK solvate (FIG. 8).

A sample of the slurry was dried over night at 100° C. in vacuum and wasthen analyzed with XRPD. This showed that it was now form F anhydrate(FIG. 1).

Preparation of Form H Ethyl Acetate Solvate and Form F Anhydrate

441 mg of Elobixibat form A monohydrate, 0.6 mL ethyl acetate and 0.6 mLn-heptane was added to a 10 mL test tube. A stirring magnet was added,the vessel was closed and was then stirred for 2 days at 62° C. Theslurry was sampled to a hot (60° C.) porous Alumina XRPD substrate andanalyzed with XRPD, which showed that it consisted of form H ethylacetate solvate (FIG. 9).

A sample of the solid was dried at 100° C. in dry nitrogen gas and wasthen analyzed with XRPD. It consisted of form F anhydrate (FIG. 2).Alternatively, the sample was dried at 100° C. in a vacuum for 7.5hours.

DVS-data for crystal modification F is given in FIG. 10. As can be seen,the moisture uptake is a linear function of % RH.

Preparation of Form E Dihydrate and Form C Anhydrate

111 mg of Elobixibat form A monohydrate was weighted into a 10 mL testtube. A magnetic flea and 2.0 mL of an acetone:water 50:50% v/v mixturewas added. This produced a gel-like material, which had to behand-stirred and vigorously shaken for a couple of minutes, before thetest-tube could be closed and put on magnetic stirring, at 21-22° C. Twodays later a sample of the white slurry was withdrawn with a Pasteurpipette and put on a cut Silicon zero background holder (ZBH). The wetsample was analyzed with XRPD, which showed that it consisted of form Edihydrate (FIG. 7).

Approximately half of the contents of the test tube was poured into acrystallization bowl, which was then dried in vacuum for 2 hours at 60°C. This sample was then analyzed with XRPD, which showed that itconsisted of form C anhydrate (FIG. 3).

DVS-data for the transformation between crystal modifications C and E isshown in FIG. 11. The lower curves, which show a significant change inmoisture between 60-70% RH, indicating the phase change frommodification C to E, are the two sorption cycles. The upper curves,which show the change in moisture for the reverse phase transitionbetween 20-10% RH, are the desorption curves. The hysterisis between thesorption and the desorption curves are due to kinetic reasons. Thetheoretical moisture amount for a dihydrate is 4.9% w/w fits well withthe four curves coinciding around 5% w/w.

Preparation of Form D Solvate and Form C Anhydrate

95 mg of Elobixibat form A monohydrate was weighted into a 10 mL testtube. A magnetic flea and 2.0 mL of ethyl acetate was added. Thisproduced a slurry, which was put on magnetic stirring, at 21-22° C. Twodays later a sample of the white slurry was withdrawn with a Pasteurpipette and put on a cut Silicon zero background holder (ZBH). The wetsample was analyzed with XRPD, which showed that it consisted of form Dsolvate (FIG. 12). The XRPD-sample was stored for 3 days at 21-22° C.and 30% relative humidity and was then re-analyzed with XRPD. It nowcontained form C anhydrate (FIG. 4).

Preparation of Form M Acetonitrile Solvate and Form L Anhydrate

99 mg of Elobixibat form A monohydrate was weighted into a 10 mL testtube. A magnetic flea and 2.0 mL of acetonitrile was added. Thisdissolved the solid but it precipitated again rapidly, thus forming aslurry. The test tube was closed and put on magnetic stirring, at 21-22°C. Two days later a sample of the white slurry was withdrawn with aPasteur pipette and put on a cut Silicon zero background holder (ZBH).The wet sample was analyzed with XRPD, which showed that it consisted ofform M acetonitrile solvate (FIG. 13).

The slurry was poured into a crystallization bowl and was left to dry upin open lab air. It was then dried 6 hours in vacuum and 100° C. Aftercooling down in a desiccator with dry silica gel it was analyzed withXRPD. It consisted of form L anhydrate (FIG. 5).

Preparation of Form N Dihydrate

A flat sample of form L anhydrate was moistened by adding drops of wateron top of it. Due to the hydrophobic properties of the solid the dropswere taken up very slowly by the solid. When the water had been taken upby the sample it was analyzed with XRPD and then consisted of form Ndihydrate (FIG. 6).

DVS-data for the transformation between crystal modifications L and N isgiven in FIG. 14. The lower curves, which show a significant change inmoisture between 40-50% RH, indicating the phase change frommodification L to N, are the two sorption cycles. The upper curves,which show the change in moisture for the reverse phase transitionbetween 20-10% RH, are the desorption curves. The hysterisis between thesorption and the desorption curves are due to kinetic reasons. Thetheoretical moisture amount for a dihydrate is 4.9% w/w fits well withthe four curves coinciding around 5% w/w.

Preparation of Form N Dihydrate Directly from a Slurry

30 mg of elobixibat was weighted into a 1.0 mL test tube. A magneticflea and 0.5 mL of a 2-propanol:water 50:50% v/v mixture was added. Thetest-tube was closed and put on magnetic stirring, at 5° C. One weeklater a sample of the white slurry was withdrawn with a Pasteur pipetteand put on a porous Corundum sample holder. The wet sample was analyzedwith XRPD, which was consistent with that of form N dihydrate.

Conclusions

A summary of the solid state behavior of elobixibat described in thisapplication is found in FIG. 15.

The invention claimed is:
 1. A crystalline form of elobixibat, which iscrystalline modification F, wherein the crystalline form has an XRPDpattern, obtained with CuKα1-radiation, with peaks at °2θ positions6.1±0.2 and 5.9±0.2, and with peaks at one or more °2θ positions of:6.6±0.2, 8.3±0.2, and 11.9±0.2.
 2. The crystalline form according toclaim 1, wherein the crystalline form has an XRPD pattern, obtained withCuKα1-radiation, with peaks at °2θ positions 6.1±0.2, 5.9±0.2, 6.6±0.2,8.3±0.2, and 11.9±0.2.
 3. The crystalline form according to claim 1,wherein the crystalline form has an XRPD pattern, obtained withCuKα1-radiation, with peaks at °2θ positions 6.1±0.2, 5.9±0.2, 6.6±0.2,8.3±0.2, and 11.9±0.2, and with peaks at one or more °2θ positions of:7.4±0.2, 10.6±0.2, 11.7±0.2, 19.2±0.2, and 19.8±0.2.
 4. A solidpharmaceutical composition comprising the crystalline form of claim 1and a pharmaceutically acceptable diluent or carrier.
 5. A method forthe treatment of a disease selected from the group consisting ofconstipation, chronic constipation, functional constipation, andconstipation predominant irritable bowel syndrome (IBS-C), in a subjectin need thereof, the method comprising administering to the subject inneed thereof a therapeutically effective amount of the crystalline formof claim
 1. 6. A method for the treatment of non-alcoholic fatty liverdisease (NAFLD), the method comprising administering to the subject atherapeutically effective amount of the crystalline form of claim
 1. 7.A method for the treatment of non-alcoholic steatohepatitis (NASH), themethod comprising administering to the subject a therapeuticallyeffective amount of the crystalline form of claim
 1. 8. A crystallineform of elobixibat, which is crystalline modification C, wherein thecrystalline form has an XRPD pattern, obtained with CuKα1-radiation,with peaks at °2θ positions 12.4±0.2 and 5.8±0.2, and with peaks at oneor more °2θ positions of: 4.8±0.2, 8.2±0.2, 9.9±0.2, 10.9±0.2, 16.6±0.2,19.8±0.2, and 20.6±0.2.
 9. The crystalline form according to claim 8,wherein the crystalline form has an XRPD pattern, obtained withCuKα1-radiation, with peaks at °2θ positions 12.4±0.2, 5.8±0.2, 4.8±0.2,8.2±0.2, 9.9±0.2, 10.9±0.2, 16.6±0.2, 19.8±0.2, and 20.6±0.2.
 10. Thecrystalline form according to claim 8, wherein the crystalline form hasan XRPD pattern, obtained with CuKα1-radiation, with peaks at °2θpositions 12.4±0.2, 5.8±0.2, 4.8±0.2, 8.2±0.2, 9.9±0.2, 10.9±0.2,16.6±0.2, 19.8±0.2, and 20.6±0.2, and with peaks at one or more °2θpositions of: 4.1±0.2, 6.7±0.2, 9.5±0.2, 12.6±0.2, and 20.7±0.2.
 11. Asolid pharmaceutical composition comprising the crystalline form ofclaim 8 and a pharmaceutically acceptable diluent or carrier.
 12. Amethod of treating a disease selected from the group consisting ofconstipation, chronic constipation, functional constipation, andconstipation predominant irritable bowel syndrome (IBS-C) in a subjectin need thereof, the method comprising administering to the subject atherapeutically effective amount of the crystalline form of claim
 8. 13.A method for the treatment of non-alcoholic fatty liver disease (NAFLD),the method comprising administering to the subject a therapeuticallyeffective amount of the crystalline form of claim
 8. 14. A method forthe treatment of non-alcoholic steatohepatitis (NASH), the methodcomprising administering to the subject a therapeutically effectiveamount of the crystalline form of claim
 8. 15. A crystalline form ofelobixibat, which is crystalline modification L, wherein the crystallineform has an XRPD pattern, obtained with CuKα1-radiation, with peaks at°2θ positions 6.4±0.2 and 12.7±0.2, and with peaks at one or more °2θpositions of: 4.2±0.2, 8.5±0.2, 10.5±0.2, 19.3±0.2, and 19.5±0.2. 16.The crystalline form according to claim 15, wherein the crystalline formhas an XRPD pattern, obtained with CuKα1-radiation, and with peaks at°2θ positions 6.4±0.2, 12.7±0.2, 4.2±0.2, 8.5±0.2, 10.5±0.2, 19.3±0.2,and 19.5±0.2.
 17. The crystalline form according to claim 15, whereinthe crystalline form has an XRPD pattern, obtained with CuKα1-radiation,with peaks at °2θ positions 6.4±0.2, 12.7±0.2, 4.2±0.2, 8.5±0.2,10.5±0.2, 19.3±0.2, and 19.5±0.2, and with peaks at one or more °2θpositions of: 4.8±0.2, 5.9±0.2, 12.1±0.2, 12.4±0.2, 13.3±0.2, 13.6±0.2,17.7±0.2, 19.9±0.2, and 21.4±0.2.
 18. A solid pharmaceutical compositioncomprising the crystalline form of claim 15 and a pharmaceuticallyacceptable diluent or carrier.
 19. A method of treating a diseaseselected from the group consisting of constipation, chronicconstipation, functional constipation, and constipation predominantirritable bowel syndrome (IBS-C) in a subject in need thereof, themethod comprising administering to the subject a therapeuticallyeffective amount of the crystalline form of claim
 15. 20. A method forthe treatment of non-alcoholic fatty liver disease (NAFLD), the methodcomprising administering to the subject a therapeutically effectiveamount of the crystalline form of claim
 15. 21. A method for thetreatment of non-alcoholic steatohepatitis (NASH), the method comprisingadministering to the subject a therapeutically effective amount of thecrystalline form of claim
 15. 22. A crystalline form of elobixibat,which is crystalline modification N, wherein the crystalline form has anXRPD pattern, obtained with CuKα1-radiation, with peaks at °2θ positions6.1±0.2, 8.0±0.2, and 12.0±0.2.
 23. The crystalline form according toclaim 22, wherein the crystalline form has an XRPD pattern, obtainedwith CuKα1-radiation, with peaks at °2θ positions 6.1±0.2, 8.0±0.2, and12.0±0.2, and with peaks at one or more °2θ positions of: 4.0±0.2,10.1±0.2, 20.1±0.2, and 21.0±0.2.
 24. The crystalline form according toclaim 22, wherein the crystalline form has an XRPD pattern, obtainedwith CuKα1-radiation, with peaks at °2θ positions 6.1±0.2, 8.0±0.2,12.0±0.2, 4.0±0.2, 10.1±0.2, 20.1±0.2, and 21.0±0.2.
 25. The crystallineform according to claim 22, wherein the crystalline form has an XRPDpattern, obtained with CuKα1-radiation, with peaks at °2θ positions6.1±0.2, 8.0±0.2, 12.0±0.2, 4.0±0.2, 10.1±0.2, 20.1±0.2, and 21.0±0.2,and with peaks at one or more °2θ positions of: 10.8±0.2, 11.4±0.2,13.3±0.2, 18.0±0.2, 18.5±0.2, and 19.7±0.2.
 26. A solid pharmaceuticalcomposition comprising the crystalline form of claim 22 and apharmaceutically acceptable diluent or carrier.
 27. A method of treatinga disease selected from the group consisting of constipation, chronicconstipation, functional constipation, and constipation predominantirritable bowel syndrome (IBS-C) in a subject in need thereof, themethod comprising administering to the subject a therapeuticallyeffective amount of the crystalline form of claim
 22. 28. A method forthe treatment of non-alcoholic fatty liver disease (NAFLD), the methodcomprising administering to the subject a therapeutically effectiveamount of the crystalline form of claim
 22. 29. A method for thetreatment of non-alcoholic steatohepatitis (NASH), the method comprisingadministering to the subject a therapeutically effective amount of thecrystalline form of claim
 22. 30. A crystalline form of elobixibat,which is crystalline modification E, wherein the crystalline form has anXRPD pattern, obtained with CuKα1-radiation, with peaks at °2θ positions6.1±0.2, 12.1±0.2, and 20.9±0.2.
 31. The crystalline form according toclaim 30, wherein the crystalline form has an XRPD pattern, obtainedwith CuKα1-radiation, with peaks at °2θ positions 6.1±0.2, 12.1±0.2 and20.9±0.2, and with peaks at one or more °2θ positions of: 8.1±0.2,10.1±0.2, 11.4±0.2, 22.3±0.2, and 22.5±0.2.
 32. The crystalline formaccording to claim 30, wherein the crystalline form has an XRPD pattern,obtained with CuKα1-radiation, with peaks at °2θ positions 6.1±0.2,12.1±0.2, 20.9±0.2, 8.1±0.2, 10.1±0.2, 11.4±0.2, 22.3±0.2, and 22.5±0.2.33. The crystalline form according to claim 30, wherein the crystallineform has an XRPD pattern, obtained with CuKα1-radiation, with peaks at°2θ positions 6.1±0.2, 12.1±0.2, 20.9±0.2, 8.1±0.2, 10.1±0.2, 11.4±0.2,22.3±0.2 and 22.5±0.2, and with peaks at one or more °2θ positions of:4.0±0.2, 18.6±0.2, 19.4±0.2, 21.1±0.2.
 34. A solid pharmaceuticalcomposition comprising the crystalline form of claim 30 and apharmaceutically acceptable diluent or carrier.
 35. A method of treatinga disease selected from the group consisting of constipation, chronicconstipation, functional constipation, and constipation predominantirritable bowel syndrome (IBS-C) in a subject in need thereof, themethod comprising administering to the subject a therapeuticallyeffective amount of the crystalline form of claim
 30. 36. A method forthe treatment of non-alcoholic fatty liver disease (NAFLD), the methodcomprising administering to the subject a therapeutically effectiveamount of the crystalline form of claim
 30. 37. A method for thetreatment of non-alcoholic steatohepatitis (NASH), the method comprisingadministering to the subject a therapeutically effective amount of thecrystalline form of claim 30.